Noise-induced hearing loss (NIHL) is a common cause of hearing loss in adults in Western industrialized countries. According to the latest National Institute of Deafness and Communication Disorders (NIDCD) report, nearly one in four (24 percent) of U.S. adults, 20 to 69 years of age, have features suggestive of NIHL. Within the military population, an estimated 60% of veterans returning home from war have hearing loss (CDC, 2013). According to Veterans Affairs (VA), noise-induced hearing injuries (NIHI) are costly and a health concern for former and current armed forces service members. Veterans Affairs disability compensation for NIHL are currently over $1 billion per year. Hearing loss has been linked to feeling of frustration, depression, social isolation, and in severe cases, cognitive decline and brain shrinkage. Thus, there is an urgent unmet need for viable treatments and preventative measures that would be readily accessible and applicable. Current rehabilitation options include the use of powerful hearing aids or highly invasive cochlear implant surgery for patients, neither of which are effective treatments. There are several anti-oxidant/steroid/supplemental vitamin clinical trials underway that target the oxidative stress pathway induced in NIHL. Some of these drugs show prevention of temporary threshold shift immediately after noise exposure. However, there are no studies that show successful treatment and restoration of NIHL. Currently, there are no FDA approved drugs in the market to treat NIHL. This STTR phase I proposal will be used to investigate the feasibility of re-purposing two clinically used FDA approved drugs for the treatment of NIHL. The combination of these drugs, which we name NT12, should allow for more rapid entry into clinical use as the safety profile of the individual drugs are already established in humans. NT12 combines two anti-inflammatory drugs that inhibit two different targets, implicated in NIHL. Preliminary data indicate that each agent, when used alone, can reduce NIHL. However, when given in combination it not only prevents NIHL, but significantly restores hearing after permanent hearing loss has already been established in the rat model. The specific aims of the project are: (1) To determine the dose response of the drug combination in preventing NIHL, and (2) to determine the feasibility and window of opportunity for using NT12 to restore hearing when administered following establishment of NIHL. Successful completion of these studies will help define the effective dose range of NT12 that will preserve at least 50% hearing, 25% preservation of ABR wave I amplitude and 20% preservation of intact synapses/IHC in the NIHL rat model. The window of opportunity will establish the time limit after traumatic noise exposure wherein NT12 treatment will be able to restore 25% hearing. The data generated from these experiments will be critical for the initial Investigational New Drug (IND) filing under an expedited regulatory path for repurposed drugs for future studies of NT12 in humans. Future Phase II studies will focus on reformulation, additional animal testing, and toxicology studies.